Disabling medical events are a major risk factor for late-life depression (LID), which in turn leads to poor functional recovery and increased mortality. Effective prevention of LLD in this setting requires research on its etiology and risk factors. Thus, we will examine genetic polymorphisms in the serotonergic system, and psychological, social, and aging-related factors as risk factors for the onset of LLD after a hip fracture, a severe and disabling event. In our pilot work, the serotonin transporter promoter polymorphism (5-HTTLPR) s allele and the 5-HT2a (-1438)A/G allele were associated with an increased likelihood of LLD and/or higher levels of depressive symptoms after hip fracture. This grant integrates clinical research methods for assessing LLD with state of the art genetic methods. We will examine association of five genetic polymorphisms in the serotonin system (5-HTTLPR, 5-HT2a (-1438)A/G, 5-HT1a (-1019)C/G, TPH-2 (1463)G/A and BDNF dinucleotide repeat) with the onset and course of LLD in 470 elderly persons who have had a hip fracture. We will collect samples for genotyping, and we will follow subjects for one year. We will longitudinally assess LLD as well as variables related to vulnerability to LLD (e.g., cognitive status, disability, medical and psychiatric comorbidity, medication use, and life events). We will collect the same information over one year on a comparison group of 100 elderly persons who have not suffered a hip fracture. We hypothesize that these polymorphisms will be associated with LLD in the hip fracture group. Beyond the testing of study hypotheses, we will model risk for LLD using both genetic and non-genetic factors (e.g., vulnerability due to personality, disposition, or prior depression;age-related changes;social support). We will replicate genetic results in a second sample of hip fracture subjects. Data and samples from this study will be made available for future genetic studies, by our group as well as other investigators. The public health relevance is great, as LLD is a devastating and difficult-to-treat illness. The proposed research will be essential to reducing the burden of LLD by improving our understanding of the etiology of this illness: additionally, findings from this research could lead risk profiling using genetic and other risk factors, a necessary step for prevention.